The objective of this proposal is to continue studies on the anticarcinogenic action of selenium using the dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model in female SD rats. The theme will be focused on the interaction between selenium and other dietary factors in the modification of mammary cancer risk. Our ultimate goal is to define a set of guidelines which optimizes the prophylactic action of selenium. In addition, we are also interested in delineating the mechanism(s) of action by which selenium inhibits tumorigenesis. Aim 1 is designed to study the interaction of selenium and vitamin E in cancer chemoprevention. Our strategy is to complete a comprehensive set of dose response experiments in the quantitative analysis of the proposed synergisms between selenium (both selenite and selenomethionine) and vitamin E in protection against mammary tumorigenesis. The kinetics of vitamin E accumulation in tissues will also be studied under these conditions. Aim 2 is designed to study the effects of protein and methionine intake on the anticarcinogenic efficacy of selenium. The basis for this study is to determine how the nutritional status of the host can affect the effectiveness of selenium in protection against cancer. Methionine is intimately involved in the metabolic fates of both selenite and selenomethionine. Consequently, methionine can exert an effect that is independent of the total protein intake. We also plan to follow up our previous observation on glutathione metabolism, specifically targeting our effort on changes of tissue GSH and GSSG levels as influenced by protein, methionine and selenium intake. Aim 3 is designed to study the effect of selenium supplemenation on tissue selenium levels and the metabolism of selenium. The purpose of this study is to test the significance of tissue selenium level as predictor of chemopreventive effectiveness. The quantitative analysis of low molecular weight selenium metabolites will be addressed in this aim. Aim 4 is designed to study the incorporation of selenium into selenoproteins as analyzed by two-dimensional gel electrophoresis. Changes in the expression of these proteins may be important in the chemopreventive action of selenium and the sensitivity to selenium inhibition of cellular proliferation.